The project goal is to quantify the roles and interactions of stimulus charge density (QD) and charge per phase (Q) in the induction of depression of neuronal excitability and loss of neurons during prolonged microstimulation in the cerebral cortex. We will examine these effects of the microstimulation in the immediate vicinity of the stimulating microelectrodes in the feline post-cruciate gyrus of the cerebral cortex, and also the remote effects in the adjacent pre-cruciate gyrus. The relations between Q, QD and the occurrence (or absence) of neuronal injury have been determined for larger macroelectrodes and has enabled development of protocols for safe and effective electrical stimulation with neural interfaces, and we propose to do the same for intraparenchymal microstimulation. Safe (and damaging) protocols for intraparenchymal microstimulation have been determined for some specific situations, but for microstimulation a systematic study has not been performed for the interactions of Q,QD and the physiologic and histologic responses. The proposed study will employ silicon substrate microelectrodes and microwire electrodes implanted chronically in the sensorimotor cortex of adult cats. We will identify combinations of Q and QD that are able to excite pyramidal tract neurons of the cerebral cortex without producing depression of neuronal excitability or loss during 200 hours of stimulation (8 hrs/day for 25 days). The range of Q to be evaluated (2 to 16 nC/phase) will span all or most of the range that is likely to be used in a clinical interface. The stimulus will be delivered for 7 hour per day, for a total of 210 hours at a pulse rate of 50 pps. This is intended to be a realistic representative of the parameters that would be used in a clinical neural interface. Since Q/QD = A, the electrodes' geometric surface area, the data from the study will define the value of A that is necessary and sufficient to allow safe and effective chronic microstimulation in the cerebral cortex using a specified charge per phase. Microstimulation within the cerebral cortex is employed widely in basic neuroscience, and there are emerging clinical applications, including cortical-level visual prostheses and auditory prostheses. In the near future, microstimulation in the sensorimotor cortex may provide somatosensory and proprioceptive feedback for close- loop control of prosthetic limbs. These and other clinical applications of intraparenchymal microstimulation will require neural interfaces that must function more- or- less continuously throughout the user's waking hours and for many years, without injury to the stimulated neurons and without significantly altering their electrical excitability. This is the range of stimulus parameters that would be used in a cortical level visual prosthesis, to convey proprioceptive or tactile information from a limb prosthesis into the sensorimotor cortex, or in a cortical- level auditory prosthesis. However, it has been shown that prolonged microstimulation in the cerebral cortex using what has been considered to be conservative values of charge density and charge per phase (4 nC/phase, 200 :C/cm2) will induce a loss of neurons adjacent to the electrodes sites, and these stimulus parameters will induce a depression of neuronal excitability (an increase in the stimulus current will be needed to induce an action potentials ) after as littl as 7 hours of continuous stimulation in the cerebral cortex. For larger macroelectrodes, the interactions of stimulus charge per phase (Q) and charge density)QD) as they relate to safe and effective neural stimulation have been well studied. However, a comparable analysis for penetrating microelectrodes that operates at greater charge density, and in very close proximity to the neurons, has not been conducted. The present study will be the first systematic investigation of the interactions between stimulus charge per phase and geometric charge density during prolonged microstimulation in the cerebral cortex. These data are necessary to inform the design of chronically implanted microelectrodes for clinical applications employing prolonged neural microstimulation. The study will employ silicon substrate microelectrodes and microwire arrays implanted chronically in the post-cruciate (sensorimotor) cortex of adult cats. We expect to identify combinations of Q and QD that are able to excite pyramidal tract neurons of the cerebral cortex without producing depression of neuronal excitability or neuronal loss during 200 hours of stimulation (8 hrs/day for 25 days). The range of Q to be evaluated (2 to 16 nC/phase) will span all or most of the range that is likely to be used in a clinical interface employing intracortical microstimulation. The stimulus will be delivered for 8 hours per day, for a total of 200 hours, at a pulse rate of 50 pps. Since Q/QD = the electrode's geometric surface area, the study will define the geometric surface area that is necessary and sufficient to allow safe and effective chronic microstimulation in the cerebral cortex using a particular charge per phase. We also will determine the propensity for the intracortical microstimulation to induce excitotoxic-like injury and neuroplasticity to neurons in an adjacent gyrus of the cerebral cortex that receives a strong excitatory input from the post cruciate gyrus.